ABSTRACT Integrins are cell surface receptors that interact with extracellular matrix (ECM) proteins to modulate cell adhesion, proliferation and survival. Experiments carried out during the last funding cycle have uncovered a novel pathway of tumor progression mediated by the [unreadable]v[unreadable]6 integrin. We found that [unreadable]v[unreadable]6 is not expressed in human and mouse normal prostate but becomes significantly upregulated in preneoplastic lesions, such as PIN (prostatic intraepithelial neoplasia), and prostatic adenocarcinoma (AdCa). Mechanistically, [unreadable]v[unreadable]6 expression results in upregulation of androgen receptor (AR) activity via activation of a JNK-mediated pathway, and, in vivo, in enhanced tumor growth ("early phases"). Our findings show, for the first time, that integrins modulate AR activity. In this pathway, we identified survivin, a bifunctional regulator of cell division and inhibitor of apoptosis, as one of the critical downstream effector molecule which becomes upregulated in cells expressing [unreadable]v[unreadable]6. In prostate cancer cells, we show that [unreadable]v[unreadable]6 is induced by TGF[unreadable] via Smad3 activation, whereas a different [unreadable]v integrin, [unreadable]v[unreadable]3, is induced by Runx2, a transcription factor known to mediate bone remodeling. In a parallel series of experiments, we have also found that [unreadable]v[unreadable]6 promotes tumor-mediated osteolysis, a crucial step in prostate cancer metastasis ("late phases"). Since [unreadable]v[unreadable]3 has been shown to promote bone gain in prostate cancer metastatic lesions, we hypothesize that the extent of bone-lesion formation is controlled by the relative expression levels of [unreadable]v[unreadable]6 and [unreadable]v[unreadable]3. We have formulated a unifying hypothesis that [unreadable]v[unreadable]6 integrin functions as an integrator of multiple signaling pathways to promote early and late phases of prostate cancer progression. Therefore, we propose that [unreadable]v[unreadable]6 functions as a novel target for molecular therapies of prostate cancer. By interrupting [unreadable]v[unreadable]6 dependent signaling and preventing the functions of its downstream effector pathways identified in the preliminary data, we will be able to identify critical requirements of this response suitable for therapeutic intervention. This model will be tested in the present renewal application, by the following aims. In Aim 1, the molecular mechanisms by which [unreadable]v[unreadable]6 activates AR will be investigated. In Aim 2, we will Investigate in vitro and in vivo the role of [unreadable]v[unreadable]6 in prostate cancer progression induced by Pten-downregulation;for this purpose, we will use Pten-null cell lines and the prostate specific Pten-null mouse model which develops PIN, cancer and metastasis. In Aim 3, to credential [unreadable]v integrins as molecular targets in prostate cancer bone lesion therapies, we will dissect the pathways by which [unreadable]v[unreadable]6 and [unreadable]v[unreadable]3 contribute to bone disease in vivo. Our long-term objective is to take advantage of this newly generated knowledge to develop novel molecular antagonists of prostate cancer progression.